She made her acting debut as transgender high school student Jules Vaughn in the HBO teen drama television series Euphoria (2019–present).

Her father is a Presbyterian minister, and their family moved between churches and congregations in New Jersey, Arizona, and finally Raleigh, North Carolina,[3][4] where she was raised.

[5] She stated that the Internet helped her cope with her gender identity, as she turned to YouTube and social media to learn about people's transition timelines.

[10][22] She first worked with Dior and Marc Jacobs, among other brands,[23] and by the end of the year she had modeled for Converse, Gucci, Helmut Lang, and Versus Versace.

[22] She has also modeled for Prada, Calvin Klein, Rick Owens, Tommy Hilfiger, Thierry Mugler, Coach, Maison Margiela, Vera Wang, Emilio Pucci, Ann Demeulemeester, and Erdem, among other houses.

[24][25][26][27] After high school, Schafer planned to attend Central Saint Martins, an arts college in London, England where she was accepted, to study clothing design for nonbinary people.

[13][22] She also wanted to open a studio and gallery for trans artists in New York, using grant money she had received from Teen Vogue for her "21 Under 21" listing.

[5][18][14] In 2019, Schafer was cast in Euphoria as a transgender high school girl, Jules Vaughn, marking her acting debut.

[18][28] She joined the show after finding a casting call for transgender girls on Instagram, which required no previous acting experience.

[35] In 2021, Schafer co-wrote an episode of Euphoria that was released between its first and second seasons, titled "Fuck Anyone Who's Not a Sea Blob".

[36][37][38] In 2021, Time named her to its Next list of "100 emerging leaders who are shaping the future", with a tribute written by Euphoria co-star Zendaya.

[47][48][49] In 2024, she was in Tilman Singer's horror movie Cuckoo,[50][51] where she plays an American teenager who reluctantly visits a creepy, remote resort in Germany with her family.

[53][54] Schafer has continued modeling throughout her acting career, appearing for Alexander McQueen, Prada and Schiaparelli, among other houses.

[55][56] She has upcoming roles in David Lowery's film Mother Mary,[57] Hideo Kojima and Jordan Peele's horror video game OD,[58] and the Amazon science fiction television series Blade Runner 2099.

[67][68] Commenting on a later Instagram post, Schafer denied being a transmedicalist or holding hatred towards non-binary people, saying that she merely felt there was "an in-balance [sic] in the visibility and space-taken up between non-binary folks and binary trans women (particularly those of color and/or those who have resulted [sic] to sex work as a means of survival) that i think deserves attention/ re-evaluation (as far as resources and platforms go) within the LGBTQ+ community".

[69] On February 27, 2024, Schafer was arrested in New York City while at a Jewish Voice for Peace protest advocating for a ceasefire in the Gaza war.